A large kindred with 17q-linked breast and ovarian cancer: Genetic, phenotypic, and genealogical analysis

Background: Mutation of a specific, but as yet unidentified, gene BRCA1 on chromosome 17q results in increased susceptibility to breast and ovarian cancer. It is important to know the effects of this gene in terms of the age-specific risks of these cancers and the potential interaction of this gene with other known risk factors. Purpose: We performed detailed studies on a large multi-generational family, in which there is known 17q-linked breast and ovarian cancer, in order to characterize the effects of the BRCA1 mutation on development of breast and ovarian cancer. Methods: Data from the Utah Population Database were used to identify a family (identified as K2082) with a cluster of premenopausal breast cancer and ovarian cancer at any age. Blood samples from 195 members of the family were obtained and these individuals were genotyped for a series of four chromosome 17q polymorphic markers. Information on reproductive history, cancer incidence and treatment, and lifestyle factors was collected on 72 women in the family by questionnaire or through contact with living relatives. Results: Odds in favor of linkage of breast and ovarian cancer in this family to the BRCA1 region of chromosome 17Q are greater than 10⁸to 1. The estimated risks for breast or ovarian cancer because of the BRCA1 mutation in this family are 40% by age 50 years and 90% by age 70. No differences between affected and unaffected older BRCA1 gene carriers were observed for a number of known epidemiologic risk factors for these cancers. The gender of the parent from whom the mutant BRCA1 allele was inherited was significantly associated with phenotypic expression (P =.04). A recombinant which places BRCA1 distal to the marker Mfd191 was observed. Conclusions: Women with the BRCA1 mutation are at increased risk of developing breast and ovarian cancer. In our study population, the mutation appears to confer a lower risk of cancer at younger ages than found in previous studies. Continued interaction with family K2082 will be useful in longitudinal follow-up studies and in studies of the psychosocial implications of providing DNA diagnosis of BRCA1. [J Natl Cancer Inst 86:200-209, 1994].